.

. , MD, FESC, FAHA - . - - -

View inside an atherosclerotic artery with severe plaque and a thrombus partially occluding the lumen (light microscopy)

JPAD study: design

JPAD trial (2008) Design Objective Multicentre, prospective, randomised, blinded, endpoint trial To examine the efficacy of aspirin for the primary prevention of atherosclerotic events in patients with type 2 diabetes

Patients
Regimen

2539 patients (mean age 65 years; 55% males) with type 2 diabetes without a history of atherosclerotic disease
1262 patients randomised to receive aspirin 81100 mg/day and 1277 patients randomised to receive placebo

Primary endpoint
Mean follow-up

Atherosclerotic events, including fatal or nonfatal IHD, fatal or nonfatal stroke, and PAD
4.4 years

IHD, ischaemic heart disease; JPAD, Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes; PAD, peripheral artery disease. 1. Ogawa H, et al. JAMA 2008;300:213441.

Section 4

Primary End Point: Total Atherosclerotic Events According to the Treatment Groups
10

8 6 %
4

Log-Rank Test, P = 0.16 HR (95% CI): 0.80 (0.581.10)

Aspirin Group 2 0 0
Nonaspirin Group (n) Aspirin Group (n)

Nonaspirin Group

1 1220 1210

2 1165 1159

3 1117 1095

4 813 806

5 135 140

Years

1277 1262

 ASA was not

effective in the primary of CV events in pts with asymptomatic PAD

Antioxidants
BMJ 2008, 337: 1840

showed no benefit as well

Relative-risk reduction and 95% CI by disease subgroup

Relative-risk reduction (%) Stroke
MI

The CAPRIE trial was a randomized, blinded study of clopidogrel versus aspirin in PAD patients at risk of ischemic events

All patients

40 30 20 10 Aspirin better

10 20 30 40 Clopidogrel better
CAPRIE. Lancet 1996;348:132939.

CAPRIE: Reduction in Fatal or Nonfatal MI

5
4 3 2 N=19,185 Aspirin *P=.008 Clopidogrel 19.2%* RRR

1
0 0 3 6 9 12 15 18

21

24 27

30

33 36

Follow-up (mo)
CAPRIE, Clopidogrel vs aspirin in Patients at Risk of Ischemic Events; MI, myocardial infarction; RRR, relative risk ratio. Cannon CP. Am J Cardiol. 2002;90:760-762. (with permission)

CAPRIE: Patients With Prior Cardiac Surgery

Primary Endpoint: MI, Stroke, Vascular Death
10
Event Rate per Year (%) 8 6 5.8% 4 2 0

9.1%

36% RRR P=.004

Aspirin (N=705)

Clopidogrel (N=775)

CAPRIE, Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events; MI, myocardial infarction; RRR, relative risk ratio. Bhatt DL, et al. Circulation. 2001;103:363-368.

CAPRIE: Clopidogrel in Diabetes

Ischemic Stroke, MI, Vascular Death, Hospitalization for Ischemic Events/Bleeding Overall Benefit P=.032; Multivariate Analysis
25 Annual Event Rate (%) 38

21
20
21.5%

Aspirin Clopidogrel

9
15
12.7%

17.7% 17.7% 15.6%

10
5 0

11.8%

Events Prevented/1000 Patients Over Aspirin

Nondiabetic

All Diabetic Patients

With Insulin

CAPRIE, Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events; MI, myocardial infarction. Bhatt DL, et al. Am J Cardiol. 2002;90:625-628. (with permission)

CAPRIE: Safety
Adverse Event GI hemorrhage, n (%) GI hemorrhage leading to hospitalization, n (%) GI ulcer, n (%) GI events overall, n (%) Clopidogrel (n=9599)
191 (2.0)

Aspirin* (n=9586)
255 (2.7)

71 (0.7)

104 (1.1)

65 (0.7)

110 (1.2)

2601 (27.1)

2859 (29.8)

* Patients with a history of aspirin intolerance were excluded from CAPRIE. CAPRIE, Clopidogrel versus aspirin in patients at risk of ischemic events; GI, gastrointestinal. Plavix (clopidogrel bisulfate) prescribing information.

TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel TRITON-TIMI 38 AHA 2007 Orlando, Florida
Disclosure Statement: The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and Womens Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.

Primary Endpoint CV Death,MI,Stroke

15
Primary Endpoint (%)

Clopidogrel
12.1 (781)

10 Prasugrel
HR 0.80 P=0.0003

9.9 (643)

HR 0.77 P=0.0001

HR 0.81 (0.73-0.90) P=0.0004 NNT= 46

ITT= 13,608

LTFU = 14 (0.1%)

0 30 60 90

180

270

360

450

Days

Clopidogrel (%, n=1,570)

UA/NSTEMI (%)

Prasugrel (%, n=1,576)

79

79

STEMI (%)
() 75 (%)

21
63 15

21
63 15

36
29
15 45 40

31*
29
15 45 40

<70kg (%) 70-90kg >90kg
*p=0.004

Wiviott SD et al. Circulation 2008; 118: 1626-1636

Diabetic Subgroup
N=3146
18 16

Clopidogrel
CV Death / MI / Stroke

17.0

Endpoint (%)

14

12.2
12 10 8 6

Prasugrel

HR 0.70 P<0.001 NNT = 46

4 2
0 0

TIMI Major NonCABG Bleeds

Clopidogrel

2.6
2.5

Prasugrel
30 60 90 180
Days

270

360

450

August 30, 2009 at 08.00 CET

PLATO study design

NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI) Clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624)

Clopidogrel If pre-treated, no additional loading dose; if naive, standard 300 mg loading dose, then 75 mg qd maintenance; (additional 300 mg allowed pre PCI)

Ticagrelor 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-PCI)

612-month exposure
Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding
PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack

Primary efficacy endpoint over time (composite of CV death, MI or stroke)

8 Cumulative incidence (%) Cumulative incidence (%) 8

Clopidogrel Ticagrelor

5.43 4.77

Clopidogrel

6.60 5.28

Ticagrelor

2
HR 0.88 (95% CI 0.771.00), p=0.045

2
HR 0.80 (95% CI 0.700.91), p<0.001

0
0
No. at risk Ticagrelor 9,333

0 31

10

20

30

90

150

210

270

330

Days after randomisation

8,942 8,827 8,763 8,673 8,688

Days after randomisation*

8,543 8,397 8,286 7,028 6,480 6,379 4,822

Clopidogrel 9,291

8,875

8,763

8,688

8,437

6,945

4,751

*Excludes patients with any primary event during the first 30 days

PLATO: Diabetes substudy

Of the 18,624 patients with ACS enrolled in the PLATO study, 4662 had a diagnosis of diabetes[Wallentin 2009:B; James 2010:A] In the diabetic subgroup of patients with ACS, outcomes were compared between:[James 2010:A,B] Diabetic vs. non-diabetic patients
96% of diabetic patients presented with type 2 diabetes

Patients with below-median vs. above-median HbA1c (median HbA1c = 6.0%)

HbA1c is a composite, long-term measure of plasma glucose control

Patients with below-median vs. above-median non-fasting serum glucose (median non-fasting serum glucose = 6.8 mmol/L)

ACS, acute coronary syndromes. Wallentin L, et al. N Engl J Med 2009;361:10451057; James S, et al. Eur Heart J 2010;31:30063016.

PLATO diabetes: Key patient characteristics

During initial hospitalisation[James 2010:A,C]
84% of diabetic patients were treated with antidiabetic medication

55.2% of diabetic patients received insulin

Almost one in four patients continued to receive insulin treatment throughout the duration of the PLATO study

Diabetic patients were more likely than non-diabetic patients to suffer from:[James 2010:D] Hypertension Dyslipidaemia Obesity Diabetic patients were less likely than non-diabetic patients to be[James 2010:D] A habitual smoker Considered for invasive treatment

James S, et al. Eur Heart J 2010;31:30063016.

PLATO diabetes: Primary composite endpoint

20

[James 2010:F,H]

CV death, MI, or stroke (%)

15

Diabetes Ticagrelor (n=2326) Clopidogrel (n=2336) HR (95% CI) = 0.88(0.761.03)

16.2% 14.1% p for interaction = 0.49

10

10.2%

8.4% 5

0 0 60 120 180 240

No diabetes Ticagrelor (n=6999) Clopidogrel (n=6952) HR (95% CI) = 0.83(0.740.93) 300 360

Days after randomisation

Primary endpoint benefit with ticagrelor was consistent with the overall PLATO trial results[Wallentin 2009:J] No interaction between diabetes status and treatment was observed (p=0.49)[James 2010:G,H]
CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction. James S, et al. Eur Heart J 2010;31:30063016.

PLATO diabetes: All-cause mortality

10

All-cause mortality (%)

Diabetes Ticagrelor (n=2326) Clopidogrel (n=2336) HR (95% CI) = 0.82(0.661.01)

[James 2010:H,I]

8.7% 7.0%

6 p for interaction = 0.66

5.0%
4 3.7% No diabetes Ticagrelor (n=6999) Clopidogrel (n=6952) HR (95% CI) = 0.77(0.650.91) 0 60 120 180 240 300 360

Days after randomisation

All-cause mortality benefit with ticagrelor was consistent with the overall PLATO trial results[Wallentin 2009:J] No interaction between diabetes status and treatment was observed (p=0.66)[James 2010:G,H]
CI, confidence interval; HR, hazard ratio. James S, et al. Eur Heart J 2010;31:30063016.

Summary of PLATO diabetes substudy: Efficacy and safety of ticagrelor

Efficacy of ticagrelor in the diabetic patient subgroup is consistent with that observed in the overall PLATO study population[James 2010:G,H] Incidence of CV death, MI or stroke and all-cause mortality in diabetic patients with ACS was numerically lower in patients treated with ticagrelor compared with clopidogrel No definitive efficacy conclusion between the treatment groups can be drawn due to the small sample size

No significant increase in major bleeding was observed in diabetic patients treated with ticagrelor compared with clopidogrel[James 2010:L,M] However, it should be noted that in the PLATO main analysis, there were higher rates of non-CABG major bleeding.

ACS, acute coronary syndromes; CV, cardiovascular; MI, myocardial infarction. James S, et al. Eur Heart J 2010;31:30063016.